Biomimetic Nanobomb for Synergistic Therapy with Inhibition of Cancer Stem Cells

Cancer stem cells (CSCs), a type of cell with self-renewal, unlimited proliferation, and insensitivity to common physical and chemical factors, are the key to cancer metastasis, recurrence, and chemo-resistance. Available CSCs inhibition strategies are mainly based on small molecule drugs, yet are limited by their off-target toxicity. The link between CSCs and non-CSCs interconversion is difficult to sever. In this work, a nanotherapeutic strategy based on MnO_x-loaded polydopamine (MnO_x/PDA) nanobombs with chemodynamic, photodynamic, photothermal and biodegradation properties to inhibit CSCs and non-CSCs concurrently is reported. The MnO_x/PDA nanobombs can directly disrupt the microenvironment and tumorigenic capacity of CSCs by generating hyperthermia, oxidative stress and alleviating hypoxia. The markers of CSCs are subsequently downregulated, leading to the clearance of CSCs. Meanwhile, the synergistic therapy mediated by MnO_x/PDA nanobombs can directly ablate the bulk tumor cells, thus cutting off the supply of CSCs transformation. For tumor targeting, MnO_x/PDA is coated with macrophage membrane. The final tumor inhibition rate of the synergistic therapy is 70.8% in colorectal cancer (CRC) model. Taken together, the present work may open up the exploration of nanomaterial-based synergistic therapy for the simultaneous elimination of therapeutically resistant CSCs and non-CSCs.     

Recent Progress in Ferroptosis Inducers for Cancer Therapy

Ferroptosis is a newly discovered form of regulated cell death that is the nexus between metabolism, redox biology, and human health. Emerging evidence shows the potential of triggering ferroptosis for cancer therapy, particularly for eradicating aggressive malignancies that are resistant to traditional therapies. Recently, there has been a great deal of effort to design and develop anticancer drugs based on ferroptosis induction. Recent advances of ferroptosis‐inducing agents at the intersection of chemistry, materials science, and cancer biology are presented. The basis of ferroptosis is summarized first to highlight the feasibility and characteristics of triggering ferroptosis for cancer therapy. A literature review of ferroptosis inducers (including small molecules and nanomaterials) is then presented to delineate their design, action mechanisms, and anticancer applications. Finally, some considerations for research on ferroptosis inducers are spotlighted, followed by a discussion on the challenges and future development directions of this burgeoning field.     

A Metal-Organic Framework (MOF) Fenton Nanoagent-Enabled Nanocatalytic Cancer Therapy in Synergy with Autophagy Inhibition

Nanocatalytic medicine has been developed recently to trigger intratumoral generation of highly toxic reactive oxygen species (ROS) for cancer therapy, which, unfortunately, suffers from compromised therapeutic efficacy due to a self-protective mechanism, autophagy, of cancer cells to mitigate oxidative damage. In this work, during the efforts of ROS generation by nanocatalytic medicine, a pharmacological autophagy inhibition strategy is implemented for augmenting ROS-induced oxidative damage for synergetic cancer therapy. An iron-containing metal-organic framework [MOF(Fe)] nanocatalyst as a peroxidase mimic is used to catalyze the generation of highly oxidizing •OH radicals specifically within cancer cells, while chloroquine is applied to deacidify lysosomes and inhibit autophagy, cutting off the self-protection pathway under severe oxidative stress. Cancer cells fail to extract their components to detoxicate and strengthen themselves, finally succumbing to the ROS-induced oxidative damage during nanocatalytic therapy. Both in vitro and in vivo results demonstrate the synergy between nanocatalytic therapy and autophagy inhibition, suggesting that such a combined strategy is applicable to amplify tumor-specific oxidative damage and may be informative to future design of therapeutic regimen.     

A Glucose/Oxygen‐Exhausting Nanoreactor for Starvation‐ and Hypoxia‐Activated Sustainable and Cascade Chemo‐Chemodynamic Therapy

Fenton reaction‐mediated chemodynamic therapy (CDT) can kill cancer cells via the conversion of H₂O₂ to highly toxic HO?. However, problems such as insufficient H₂O₂ levels in the tumor tissue and low Fenton reaction efficiency severely limit the performance of CDT. Here, the prodrug tirapazamine (TPZ)‐loaded human serum albumin (HSA)–glucose oxidase (GOx) mixture is prepared and modified with a metal–polyphenol network composed of ferric ions (Fe³⁺) and tannic acid (TA), to obtain a self‐amplified nanoreactor termed HSA–GOx–TPZ–Fe³⁺–TA (HGTFT) for sustainable and cascade cancer therapy with exogenous H₂O₂ production and TA‐accelerated Fe³⁺/Fe²⁺ conversion. The HGTFT nanoreactor can efficiently convert oxygen into HO? for CDT, consume glucose for starvation therapy, and provide a hypoxic environment for TPZ radical‐mediated chemotherapy. Besides, it is revealed that the nanoreactor can significantly elevate the intracellular reactive oxygen species content and hypoxia level, decrease the intracellular glutathione content, and release metal ions in the tumors for metal ion interference therapy (also termed “ion‐interference therapy” or “metal ion therapy”). Further, the nanoreactor can also increase the tumor’s hypoxia level and efficiently inhibit tumor growth. It is believed that this tumor microenvironment‐regulable nanoreactor with sustainable and cascade anticancer performance and excellent biosafety represents an advance in nanomedicine.     

Antiferromagnetic Pyrite as the Tumor Microenvironment‐Mediated Nanoplatform for Self‐Enhanced Tumor Imaging and Therapy

Several decades of research have identified the specific tumor microenvironment (TME) to develop promising nanotheranostics, such as pH‐sensitive imaging, acidity‐sensitive starving therapy, and hydrogen peroxide‐activated chemotherapy, etc. Herein, a novel TME‐mediated nanoplatform employing antiferromagnetic pyrite nanocubes is presented, exploiting the intratumoral, overproduced peroxide for self‐enhanced magnetic resonance imaging (MRI) and photothermal therapy (PTT)/chemodynamic therapy (CDT). Through the activation of excessive peroxide in the tumor microenvironment, pyrite can lead to in situ surface oxidation and generate hydroxyl radicals to kill tumor cells (i.e., CDT). The increase of the valence state of surface Fe significantly promotes the performance of MRI accompanied by CDT. Furthermore, the localized heat by photothermal treatment can accelerate the intratumoral Fenton process, enabling a synergetic PTT/CDT. To our best knowledge, this is the first study to use the TME‐response valence‐variable strategy based on pyrite for developing a synergetic nanotheranostic, which will open up a new dimension for the design of other TME‐based anticancer strategies.     

Dendritic Plasmonic CuPt Alloys for Closed-Loop Multimode Cancer Therapy with Remarkably Enhanced Efficacy

The outcome of laser-triggered plasmons-induced phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is significantly limited by the hypoxic tumor microenvironment and the upregulation of heat shock proteins (HSPs) in response to heat stress. Mitochondria, the biological battery of cells, can serve as an important breakthrough to overcome these obstacles. Herein, dendritic triangular pyramidal plasmonic CuPt alloys loaded with heat-sensitive NO donor N, N′-di-sec-butyl-N, N′-dinitroso-1,4-phenylenediamine (BNN) is developed. Under 808 nm laser irradiation, plasmonic CuPt can generate superoxide anion free radicals (·O₂⁻) and heat simultaneously. The heat generated can then trigger the release of NO gas, which not only enables gas therapy but also damages the mitochondrial respiratory chain. Impaired mitochondrial respiration leads to reduced oxygen consumption and insufficient intracellular ATP supply, which effectively alleviates tumor hypoxia and undermines the synthesis of HSPs, in turn boosting plasmonic CuPt-based PDT and mild PTT. Additionally, the generated NO and ·O₂⁻ can react to form more cytotoxic peroxynitrite (ONOO⁻). This work describes a plasmonic CuPt@BNN (CPB) triggered closed-loop NO gas, free radicals, and mild photothermal therapy strategy that is highly effective at reciprocally promoting antitumor outcomes.     

Nanocatalysts‐Augmented and Photothermal‐Enhanced Tumor‐Specific Sequential Nanocatalytic Therapy in Both NIR‐I and NIR‐II Biowindows

The tumor microenvironment (TME) has been increasingly recognized as a crucial contributor to tumorigenesis. Based on the unique TME for achieving tumor‐specific therapy, here a novel concept of photothermal‐enhanced sequential nanocatalytic therapy in both NIR‐I and NIR‐II biowindows is proposed, which innovatively changes the condition of nanocatalytic Fenton reaction for production of highly efficient hydroxyl radicals (?OH) and consequently suppressing the tumor growth. Evidence suggests that glucose plays a vital role in powering cancer progression. Encouraged by the oxidation of glucose to gluconic acid and H₂O₂ by glucose oxidase (GOD), an Fe₃O₄/GOD‐functionalized polypyrrole (PPy)‐based composite nanocatalyst is constructed to achieve diagnostic imaging‐guided, photothermal‐enhanced, and TME‐specific sequential nanocatalytic tumor therapy. The consumption of intratumoral glucose by GOD leads to the in situ elevation of the H₂O₂ level, and the integrated Fe₃O₄ component then catalyzes H₂O₂ into highly toxic ?OH to efficiently induce cancer‐cell death. Importantly, the high photothermal‐conversion efficiency (66.4% in NIR‐II biowindow) of the PPy component elevates the local tumor temperature in both NIR‐I and NIR‐II biowindows to substaintially accelerate and improve the nanocatalytic disproportionation degree of H₂O₂ for enhancing the nanocatalytic‐therapeutic efficacy, which successfully achieves a remarkable synergistic anticancer outcome with minimal side effects.     

Prodrug‐Based Versatile Nanomedicine for Enhancing Cancer Immunotherapy by Increasing Immunogenic Cell Death

Nanoparticle‐based tumor immunotherapy has emerged to show great potential for simultaneously regulating the immunosuppressive tumor microenvironment, reducing the unpleasant side effects, and activating tumor immunity. Herein, an excipient‐free glutathione/pH dual‐responsive prodrug nanoplatform is reported for immunotherapy, simply by sequentially liberating 5‐aminolevulinic acid and immunogenically inducing doxorubicin drug molecules, which can leverage the acidity and reverse tumor microenvironment. The obtained nanoplatform effectively boosts the immune system by promoting dendritic cell maturation and reducing the number of immune suppressive immune cells, which shows the enhanced adjunctive effect of anti‐programmed cell death protein 1 therapy. Overall, the prodrug‐based immunotherapy nanoplatform may offer a reliable strategy for improving synergistic antitumor efficacy.     

A Nanoplatform with Precise Control over Release of Cargo for Enhanced Cancer Therapy

The development of a nanocarrier delivery system having both sufficient stability in blood circulation and a rapid drug release profile at target sites remains a major challenge in cancer therapy. Here, a multifunctional star‐shaped micellar system with a precisely spatiotemporal control of releasing encapsulated agents is developed by mixing a photoinitiated crosslinking amphiphilic copolymer with a phenylboronic acid (PBA)‐functionalized redox‐sensitive amphiphilic copolymer for the first time. The combination of the functional polymers effectively resolves the contradiction that the micellar system cannot release the rapid drug release in cells when it possesses an extreme stability that is often required in blood circulation. In this system, the inner core polymers are photo‐crosslinked, endowing a stable micelle matrix structure; the end groups of the hydrophilic segments are decorated with PBA ligands, providing an active targeting ability; disulfide bonds in the micellar matrix impart a redox‐responsive trigger for the prompt intracellular release of drugs. As a result, with a relatively low DOX dosage (2 mg kg^?1 per injection) the in vivo antitumor effect on H22‐bearing BALB/c mice shows that the micelles have a high therapeutic efficacy against solid tumors while minimal side effects against normal tissues.     

Light‐Induced ROS Generation and 2‐DG‐Activated Endoplasmic Reticulum Stress by Antitumor Nanosystems: An Effective Combination Therapy by Regulating the Tumor Microenvironment

A multimodal cancer therapeutic nanoplatform is reported. It demonstrates a promising approach to synergistically regulating the tumor microenvironment. The combination of intracellular reactive oxygen species (ROS) generated by irradiation of photosensitizer and endoplasmic reticulum (ER) stress induced by 2‐deoxy‐glucose (2‐DG) has a profound effect on necrotic or apoptotic cell death. Especially, targeting metabolic pathway by 2‐DG is a promising strategy to promote the effect of photodynamic therapy and chemotherapy. The nanoplatform can readily release its cargoes inside cancer cells and combines the advantages of ROS‐sensitive releasing chemotherapeutic drugs, upregulating apoptosis pathways under ER stress, light‐induced generation of cytotoxic ROS, achieving tumor accumulation, and in vivo fluorescence imaging capability. This work highlights the importance of considering multiple intracellular stresses as design parameters for nanoscale functional materials in cell biology, immune response, as well as medical treatments of cancer, Alzheimer's disease, etc.     

A Multifunctional Cascade Bioreactor Based on Hollow‐Structured Cu2MoS4 for Synergetic Cancer Chemo‐Dynamic Therapy/Starvation Therapy/Phototherapy/Immunotherapy with Remarkably Enhanced Efficacy

The unique tumor microenvironment (TME) facilitates cancer proliferation and metastasis, and it is hard to cure cancer completely via monotherapy. Herein, a multifunctional cascade bioreactor based on hollow mesoporous Cu₂MoS₄ (CMS) loaded with glucose oxidase (GOx) is constructed for synergetic cancer therapy by chemo‐dynamic therapy (CDT)/starvation therapy/phototherapy/immunotherapy. The CMS harboring multivalent elements (Cu^1+/2+, Mo^4+/6+) exhibit Fenton‐like, glutathione (GSH) peroxidase‐like and catalase‐like activity. Once internalized into the tumor, CMS could generate ·OH for CDT via Fenton‐like reaction and deplete overexpressed GSH in TME to alleviate antioxidant capability of the tumors. Moreover, under hypoxia TME, the catalase‐like CMS could react with endogenous H₂O₂ to generate O₂ for activating the catalyzed oxidation of glucose by GOx for starvation therapy accompanied with the regeneration of H₂O₂. The regenerated H₂O₂ can devote to Fenton‐like reaction for realizing GOx‐catalysis‐enhanced CDT. Meanwhile, the CMS under 1064 nm laser irradiation shows remarkable tumor‐killing ability by phototherapy due to its excellent photothermal conversion efficiency (η = 63.3%) and cytotoxic superoxide anion (·O₂^?) generation performance. More importantly, the PEGylated CMS@GOx‐based synergistic therapy combined with checkpoint blockade therapy could elicit robust immune responses for both effectively ablating primary tumors and inhibiting cancer metastasis.     

Glutathione Depletion in a Benign Manner by MoS2‐Based Nanoflowers for Enhanced Hypoxia‐Irrelevant Free‐Radical‐Based Cancer Therapy

Tumor hypoxia significantly diminishes the efficacy of reactive oxygen species (ROS)‐based therapy, mainly because the generation of ROS is highly oxygen dependent. Recently reported hypoxia‐irrelevant radical initiators (AIBIs) exhibit promising potential for cancer therapy under different oxygen tensions. However, overexpressed glutathione (GSH) in cancer cells would potently scavenge the free radicals produced from AIBI before their arrival to the specific site and dramatically limit the therapeutic efficacy. A synergistic antitumor platform (MoS₂@AIBI‐PCM nanoflowers) is constructed by incorporating polyethylene‐glycol‐functionalized molybdenum disulfide (PEG‐MoS₂) nanoflowers with azo initiator and phase‐change material (PCM). Under near‐infrared laser (NIR) irradiation, the photothermal feature of PEG‐MoS₂ induces the decomposition of AIBI to produce free radicals. Furthermore, PEG‐MoS₂ can facilitate GSH oxidation without releasing toxic metal ions, greatly promoting tumor apoptosis and avoiding the introduction of toxic metal ions. This is the first example of the use of intelligent MoS₂‐based nanoflowers as a benign GSH scavenger for enhanced cancer treatment.     

Dual Intratumoral Redox/Enzyme‐Responsive NO‐Releasing Nanomedicine for the Specific,High‐Efficacy,and Low‐Toxic Cancer Therapy

Chemotherapy suffers numbers of limitations including poor drug solubility, nonspecific biodistribution, and inevitable adverse effects on normal tissues. Tumor‐targeted delivery and intratumoral stimuli‐responsive release of drugs by nanomedicines are considered to be highly promising in solving these problems. Compared with traditional chemotherapeutic drugs, high concentration of nitric oxide (NO) exhibits unique anticancer effects. The development of tumor‐targeting and intratumoral microenvironment‐responsive NO‐releasing nanomedicines is highly desired. Here a novel kind of organic–inorganic composite nanomedicine (QM‐NPQ@PDHNs) is presented by encapsulating a glutathione S‐transferases π (GSTπ)‐responsive drug O²‐(2,4‐dinitro‐5‐{[2‐(β‐d ‐galactopyranosyl olean‐12‐en‐28‐oate‐3‐yl)‐oxy‐2‐oxoethyl] piperazine‐1‐yl} phenyl) 1‐(methylethanolamino)diazen‐1‐ium‐1,2‐dilate (NPQ) as NO donor and an aggregation‐induced‐emission (AIE) red fluorogen QM‐2 into the cores of the hybrid nanomicelles (PEGylated disulfide‐doped hybrid nanocarriers (PDHNs)) with glutathione (GSH)‐responsive shells. The QM‐NPQ@PDHN nanomedicine is able to respond to the intratumoral over‐expressed GSH and GSTπ, resulting in the responsive biodegradation of the protective organosilica shell and NPQ release, and subsequent NO release within the tumor, respectively, and thus normal organs remain unaffected. This work demonstrates a paradigm of dual intratumoral redox/enzyme‐responsive NO‐release nanomedicine for tumor‐specific and high‐efficacy cancer therapy.